Galenic formulations of organic compounds

ABSTRACT

The present invention relates to a solid oral dosage form comprising a therapeutically effective amount of aliskiren or a pharmaceutically acceptable salt thereof, and wherein the active ingredient is present in an amount of more than 46% by weight based on the total weight of the oral dosage form.

This application claims benefit of U.S. Provisional Application60/553,878, filed Mar. 17, 2004.

The present invention relates to solid oral dosage forms comprising anorally active renin inhibitor, aliskiren, or a pharmaceuticallyacceptable salt thereof, as the active ingredient in a suitable carriermedium. In particular, the present invention provides galenicformulations comprising aliskiren, preferably, a hemi-fumarate saltthereof, alone or in combination with another active agent. The presentinvention also relates to the processes for their preparation and totheir use as medicaments.

In the following the term “aliskiren”, if not defined specifically, isto be understood both as the free base and as a salt thereof, especiallya pharmaceutically acceptable salt thereof, most preferably ahemi-fumarate thereof.

Renin released from the kidneys cleaves angiotensinogen in thecirculation to form the decapeptide angiotensin I. This is in turncleaved by angiotensin converting enzyme in the lungs, kidneys and otherorgans to form the octapeptide angiotensin II. The octapeptide increasesblood pressure both directly by arterial vasoconstriction and indirectlyby liberating from the adrenal glands the sodium-ion-retaining hormonealdosterone, accompanied by an increase in extracellular fluid volume.Inhibitors of the enzymatic activity of renin bring about a reduction inthe formation of angiotensin I. As a result a smaller amount ofangiotensin II is produced. The reduced concentration of that activepeptide hormone is the direct cause of, e.g., the antihypertensiveeffect of renin inhibitors. Accordingly, renin inhibitors, or saltsthereof, may be employed, e.g., as antihypertensives or for treatingcongestive heart failure.

The renin inhibitor, aliskiren, in particular, a hemi-fumarate thereof,is known to be effective in the treatment of reducing blood pressureirrespective of age, sex or race and is also well tolerated. Aliskirenin form of the free base is represented by the following formula

and chemically defined as2(S),4(S),5(S),7(S)—N-(3-amino-2,2-dimethyl-3-oxopropyl)-2,7-di(1-methylethyl)-4-hydroxy-5-amino-8-[4-methoxy-3-(3-methoxy-propoxy)phenyl]-octanamide.As described above, most preferred is the hemi-fumarate salt thereofwhich is specifically disclosed in EP 678503 A as Example 83.

The oral administration of such pharmaceutical agents as tablets orcapsules has certain advantages over parenteral administration such asi.v. or i.m. Diseases requiring treatment with painful injectableformulations are considered to be more serious than those conditionswhich can be treated with oral dosage forms. However, the majoradvantage with oral formulations is held to be their suitability forself administration whereas parenteral formulations have to beadministered in most cases by a physician or paramedical personnel.

However, aliskiren is difficult to formulate and heretofore it has notbeen possible to make oral formulations in the form of tablets in areliable and robust way. In a galenic formulation comprising aliskiren,or a pharmaceutically acceptable salt thereof, a high amount is normallyheeded of the drug substance (DS) with properties that make theformulation of tablets difficult.

For example, aliskiren has a needle shaped crystal habit, which has anegative influence on the bulk properties of the drug substance, e.g.,flow properties and bulk density. The compression behavior of the drugsubstance is poor, leading to weak interparticulate bonds andpolymorphism changes under pressure. Aliskiren has a strong elasticcomponent that also leads to weakening of interparticulate bonds. Thehigh dose (up to 300 or 600 mg of the free base per tablet) makes a highdrug loading necessary in order to achieve a reasonable tablet size.

The drug substance quality is very variable with effect on theprocessability of a tablet, e.g., particle size distribution, bulkdensity, flowability, wetting behavior, surface area and stickingtendency. Moreover, aliskiren is highly hygroscopic. In contact withwater, the drug substance polymorphism changes to an amorphous state,which shows inferior stability compared to the crystalline state. Thecombination of these hurdles makes a standard tablet manufacturingprocess extremely difficult.

Direct compression is not a feasible option for routine productionbecause of, e.g., the high hygroscopicity, the needle shaped particlestructure, the poor flowability with resulting processability problemsand dose uniformity problems. A roller compaction process leads to areduction of the high bulk volume of the drug substance. Yet, thepre-compression of the drug substance during roller compaction makes afurther compression into tablets with sufficient hardness and resistanceto friability without a high amount of excipients extremely difficultdue to the low compressibility of the drug substance. A tablet with adrug load of aliskiren higher than ca. 35% has been found not to lead torobust tablets (e.g. friability, hardness) and a robust process (e.g.sticking and picking during roller compaction and tabletting).

Accordingly, a suitable and robust galenic formulation overcoming theabove problems relating to the properties of aliskiren need to bedeveloped.

The present invention has solved the above problems resulting in arobust formulation avoiding all the above disadvantages and in a processsuitable for large-scale manufacture of solid oral dosage forms.

The present invention relates to a solid oral dosage form comprising atherapeutically effective amount of aliskiren, or a pharmaceuticallyacceptable salt thereof, and wherein the active ingredient is present inan amount of more than 46% by weight based on the total weight of theoral dosage form, either dependent on or not dependent on any coating orcapsule material used.

If not dependent on any coating or capsule used, the active ingredientis present in an amount of more than 48% by weight based on the totalweight of the oral dosage form. If dependent on any coating or capsuleused, the active ingredient is present in an amount of more than 46% byweight based on the total weight of the oral dosage form.

In a preferred embodiment of the present invention, the active agent ispresent in an amount ranging from 46 to 60% by weight based on the totalweight of the oral dosage form.

In another preferred embodiment of the present invention, the activeagent is present in an amount of more than 46% up to 56% by weight basedon the total weight of the oral dosage form.

In a solid oral dosage form according to the present invention whereinthe active agent consists entirely of aliskiren, or a pharmaceuticallyacceptable salt thereof, it is preferred if the active agent is presentin an amount ranging from about 75 mg to about 600 mg of the free baseper unit dosage form.

In a preferred embodiment of the present invention, the active agentconsists entirely of aliskiren, or a pharmaceutically acceptable saltthereof, and is present in an amount ranging from about 75 to about 300mg of the free base per unit dosage form.

In a further preferred embodiment of the present invention, the dosageof aliskiren is in the form of a hemi-fumarate thereof and is present inan amount of about 83, about 166, about 332 or about 663 mg per unitdosage form.

Solid oral dosage forms according to the present invention provide forthe administration of the active ingredient in a smaller oral form thanwas heretofore possible for a given unit dose of the active agent.Furthermore, the oral dosage forms obtained are stable both to theproduction process and during storage, e.g., for about 2 years inconventional packaging, e.g., sealed aluminium blister packs.

The terms “effective amount” or “therapeutically effective amount”refers to the amount of the active ingredient or agent which halts orreduces the progress of the condition being treated or which otherwisecompletely or partly cures or acts palliatively on the condition.

Aliskiren, or a pharmaceutically acceptable salt thereof, can, e.g., beprepared in a manner known per se, especially as described in EP 678503A, e.g., in Example 83.

A solid oral dosage form comprises a capsule or more preferably a tabletor a film-coated tablet.

A solid oral dosage form according to the invention comprises additivesor excipients that are suitable for the preparation of the solid oraldosage form according to the present invention. Tabletting aids,commonly used in tablet formulation can be used and reference is made tothe extensive literature on the subject, see in particular Fiedler's“Lexicon der Hilfstoffe”, 4th Edition, ECV Aulendorf 1996, which isincorporated herein by reference. These include, but are not limited to,fillers, binders, disintegrants, lubricants, glidants, stabilisingagents, fillers or diluents, surfactants, film-formers, softeners,pigments and the like.

In a preferred embodiment the solid oral dosage form according to thepresent invention comprises as an additive a filler.

In a preferred embodiment the solid oral dosage form according to thepresent invention comprises as an additive, in addition to a filler, adisintegrant.

In a preferred embodiment the solid oral dosage form according to thepresent invention comprises as an additive, in addition to a filler anda disintegrant, a lubricant.

In a preferred embodiment the solid oral dosage form according to thepresent invention comprises as an additive, in addition to a filler, adisintegrant and a lubricant, a glidant.

In a preferred embodiment the solid oral dosage form according to thepresent invention comprises as an additive, in addition to a filler, adisintegrant, a lubricant and a glidant, a binder.

As fillers one can particularly mention starches, e.g., potato starch,wheat starch, corn starch, hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methyl cellulose (HPMC) and, preferably,microcrystalline cellulose, e.g., products available under theregistered trade marks AVICEL, FILTRAK, HEWETEN or PHARMACEL.

As binders for wet granulation, one can particularly mentionpolyvinylpyrrolidones (PVP), e.g., PVP K 30, HPMC, e.g., viscositygrades 3 or 6 cps, and polyethylene glycols (PEG), e.g., PEG 4000. Amost preferred binder is PVP K 30.

As disintegrants one can particularly mention carboxymethylcellulosecalcium (CMC-Ca), carboxymethylcellulose sodium (CMC-Na), crosslinkedPVP (e.g. CROSPOVIDONE, POLYPLASDONE or KOLLIDON XL), alginic acid,sodium alginate and guar gum, most preferably crosslinked PVP(CROSPOVIDONE), crosslinked CMC (Ac-Di-Sol), carboxymethylstarch-Na(PIRIMOJEL and EXPLOTAB). A most preferred disintegrant is CROSPOVIDONE.

As glidants one can mention in particular colloidal silica, such ascolloidal silicon dioxide, e.g., AEROSIL, magnesium (Mg) trisilicate,powdered cellulose, starch, talc and tribasic calcium phosphate orcombinations of these with fillers or binders, e.g., silicifiedmicrocrystalline cellulose (PROSOLV). A most preferred glidant iscolloidal silicon dioxide (e.g. AEROSIL 200).

As fillers or diluents one can mention confectioner's sugar,compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol,microcrystalline cellulose, in particular, having a density of about0.45 g/cm³, e.g., AVICEL, powdered cellulose, sorbitol, sucrose andtalc. A most preferred filler is microcrystalline cellulose.

As lubricants one can mention in particular Mg stearate, aluminum (Al)or Ca stearate, PEG 4000 to 8000 and talc, hydrogenated castor oil,stearic acid and salts thereof, glycerol esters, Na-stearylfumarate,hydrogenated cotton seed oil and others. A most preferred lubricant isMg stearate.

Additives to be used as filmcoating materials comprise polymers such asHPMC, PEG, PVP, polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA),polyvinyl alcohol (PVA), and sugar as film formers. A most preferredcoating material is HPMC, especially HPMC 3 cps (preferred amount 5-6mg/cm²), and mixtures thereof with further additives, e.g., thoseavailable under the registered trade mark OPADRY. Further additivescomprise pigments, dies, lakes, most preferred TiO₂ and iron oxides,anti-tacking agents like talk and softeners like PEG 3350, 4000, 6000,8000 or others. Most preferred additives are talk and PEG 4000.

The present invention likewise relates to a solid oral dosage formcomprising a therapeutically effective amount of aliskiren, or apharmaceutically acceptable salt thereof, as an active agent, and afiller as an additive. Further additives include, but are not limitedto, binders, disintegrants, lubricants, glidants, stabilising agents,diluents, surfactants, film formers, pigments, softeners and antitackingagents and the like. The amounts of the active ingredient and furtheradditives are preferably those as defined above.

The present invention likewise relates to a solid oral dosage formcomprising a therapeutically effective amount of aliskiren, or apharmaceutically acceptable salt thereof, as an active agent, and afiller and a disintegrant as additives. Further additives include, butare not limited to, binders, lubricants, glidants, stabilising agents,diluents, surfactants, film formers, pigments, softeners and antitackingagents and the like. The amounts of the active ingredient and furtheradditives are preferably those as defined herein above.

The present invention likewise relates to a solid oral dosage formcomprising a therapeutically effective amount of aliskiren, or apharmaceutically acceptable salt thereof, as an active agent, and afiller, a disintegrant and a lubricant as additives. Further additivesinclude, but are not limited to, binders, glidants, stabilising agents,diluents, surfactants, film formers, pigments, softeners and antitackingagents and the like. The amounts of the active ingredient and furtheradditives are preferably those as defined herein above.

The present invention likewise relates to a solid oral dosage formcomprising a therapeutically effective amount of aliskiren, or apharmaceutically acceptable salt thereof, as an active agent, and afiller, a disintegrant, a lubricant and a glidant as additives. Furtheradditives include, but are not limited to, binders, stabilising agents,diluents, surfactants, film formers, pigments, softeners and antitackingagents and the like. The amounts of the active ingredient and furtheradditives are preferably those as defined herein above.

The present invention likewise relates to a solid oral dosage formcomprising a therapeutically effective amount of aliskiren, or apharmaceutically acceptable salt thereof, as an active agent, and afiller, a disintegrant, a lubricant, a glidant and a binder asadditives. Further additives include, but are not limited to,stabilising agents, diluents, surfactants, film formers, pigments,softeners and antitacking agents and the like. The amounts of the activeingredient and further additives are preferably those as defined hereinabove.

One or more of these additives can be selected and used by a personskilled in the art having regard to the particular desired properties ofthe solid oral dosage form by routine experimentation and without anyundue burden.

The amount of each type of additive employed, e.g., glidant, binder,disintegrant, filler or diluent and lubricant or film coat may varywithin ranges conventional in the art. Thus, for example, the amount oflubricant may vary within a range of from 0.2 to 5% by weight, inparticular, for Mg stearate from 0.5 to 2.0% by weight, e.g., from 0.8to 1.5% by weight; the amount of binder may vary within a range of from0 to about 20% by weight, e.g., from 3 to 4% by weight; the amount ofdisintegrant may vary within a range of from 0 to about 20% by weight,e.g., from 13.5 to 16% by weight; the amount of filler or diluent mayvary within a range of from 0 to about 80% by weight, e.g., from 20 to32% by weight; whereas the amount of glidant may vary within a range offrom 0 to about 5% by weight, e.g. from 0.4 to 0.6% by weight; and theamount of film coat may vary within a range of 0 to 20 mg/cm², e.g. 4 to7 mg/cm².

It is a characteristic of the present solid oral dosage forms that theycontain only a relatively small amount of additives given the highcontent of the active agent. This enables the production of physicallysmall unit dosage forms. The total amount of additives in a givenuncoated unit dosage may be about 60% or less by weight based on thetotal weight of the solid oral dosage form, more particularly about 54%or less. Preferably, the additive content is in the range of about 35 to55% by weight, more particularly, the additive content ranges from about50 to about 52% by weight.

A preferred amount of a filler, especially of microcrystallinecellulose, ranges from about 20 to 32% by weight per unit dosage form.

A preferred amount of a binder, especially of PVP K 30, ranges fromabout 3 to 4% by weight per unit dosage form.

A preferred amount of a disintegrant, especially of CROSPOVIDONE, rangesfrom about 13.5 to 15% by weight per unit dosage form.

A preferred amount of a glidant, especially of colloidal silicondioxide, ranges from about 0.4 to 0.6% by weight per unit dosage form.

A preferred amount of a lubricant, especially of Mg stearate, rangesfrom about 0.8 to 1.5% by weight per unit dosage form.

A preferred amount of a film coat, especially of HPMC 3 cps, ranges fromabout 4 to 7 mg/cm² per unit dosage form.

Preferred amounts of aliskiren and additives are further shown in theillustrative Examples.

The absolute amounts of each additive and the amounts relative to otheradditives is similarly dependent on the desired properties of the solidoral dosage form and may also be chosen by the skilled artisan byroutine experimentation without undue burden. For example, the solidoral dosage form may be chosen to exhibit accelerated and/or delayedrelease of the active agent with or without quantitative control of therelease of active agent.

Thus, where accelerated release is desired a disintegrant such ascrosslinked PVP, e.g., those products available under the registeredtrade marks POLYPLASDONE XL or KOLLIDON CL, in particular, having amolecular weight in excess of 1,000,000, more particularly, having aparticle size distribution of less than 400 microns or, preferably, lessthan 74 microns, or comprising reactive additives (effervescentmixtures) that effect rapid disintegration of the tablet in the presenceof water, for example so-called effervescent tablets that contain anacid in solid form, typically citric acid, which acts in water on a basecontaining chemically combined carbon dioxide, for example sodiumhydrogencarbonate or sodium carbonate, and releases carbon dioxide.

Whereas if delayed release is desired one may employ coating technologyfor multiparticulates (e.g. pellets, minitablets), wax matrix systems,polymer matrix tablets or polymer coatings or other technologiesconventional in the art.

Quantitative control of the release of the active agent can be achievedby conventional techniques known in the art. Such dosage forms are knownas oral osmotic systems (e.g. OROS), coated tablets, matrix tablets,press-coated tablets, multilayer tablets and the like.

In a solid oral dosage form wherein the active agent consists entirelyof aliskiren, or a pharmaceutically acceptable salt thereof, or acombination of aliskiren with other active pharmaceutical ingredients,preferred additives are microcrystalline cellulose,hydroxypropylcellulose, crosslinked PVP, PVP, PEG, CMC-Na or CMC-Ca, Mgstearate, Ca stearate or Al stearate, anhydrous colloidal silica, talc,titanium dioxide and iron oxide pigments. The amounts of additiveemployed will depend upon how much active agent is to be used. Thestearate, e.g., Mg stearate is preferably employed in amounts of 0.8 to1.5% by weight. Whereas the silica is preferably employed in an amountof from 0.4 to 0.6% by weight.

The amount of aliskiren in the form of the hemi-fumarate thereof withinthe total weight of the uncoated unit dosage form ranges, preferably,from about 83 to about 663 mg, most preferably, the amount of aliskirenhemi-fumarate is about 83, about 166 or about 332 mg per unit dosageform.

The amount of the binder within the total weight of the uncoated unitdosage form is preferably from 2 to 5%, most preferably from 3 to 4% byweight per unit dosage form.

The amount of the disintegrant within total weight of the uncoated unitdosage form is preferably from 0 to 20%, most preferably from 13.5 to16% by weight per unit dosage form.

The amount of the glidant within the total weight of the uncoated unitdosage form is preferably from 0 to 5%, most preferably from 0.4 to 0.6%by weight per unit dosage form.

The amount of the lubricant within the total weight of the uncoated unitdosage form is preferably from 0.2 to 5%, most preferably from 0.8 to1.5% for Mg stearate by weight per unit dosage form.

A preferred amount of a film coat, especially of HPMC 3 cps, is fromabout 4 to about 7 mg/cm² per unit dosage form.

The weight ratio of aliskiren to the binder preferably ranges from about8:1 to about 25:1, more preferably from about 11:1 to about 15:1. Mostpreferably, the weight ratio is about 12.5:1.

The weight ratio of aliskiren to the disintegrant preferably ranges fromabout 2:1 to about 4:1, more preferably from about 2.5:1 to about 3.7:1.Most preferably, the weight ratio is about 3.1:1.

The weight ratio of aliskiren to the glidant preferably ranges fromabout 75:1 to about 125:1, more preferably from about 80:1 to about90:1. Most preferably, the weight ratio is about 83.3:1.

The weight ratio of aliskiren to the lubricant preferably ranges fromabout 25:1 to about 63:1, more preferably from about 30:1 to about 50:1.Most preferably, the weight ratio is about 30:1.

The solid oral dosage forms according to the present invention may alsobe in the form of film-coated tablets or dragées in which case the solidoral dosage form is provided with a coating typically a polymer likeHPMC, PVP or the like, sugar, shellac or other film-coating entirelyconventional in the art. Attention is drawn to the numerous knownmethods of coating employed in the art, e.g., spray coating in afluidized bed, e.g., by the known methods using apparatus available fromAeromatic, Glatt, Wurster or Hüttlin, in a perforated pan coater, e.g.,by the known methods using apparatus from Accela Cota, Glatt, Driam orothers, or other methods conventional in the art. The additives commonlyused in confectioning may be employed in such methods.

A further embodiment of the present invention is a process for themanufacture of a solid oral dosage form according to the presentinvention.

Wet granulation of aliskiren with excipients using water and/or anaqueous binder solution leads to a change in polymorphism of the drugsubstance which changes partly to the amorphous state and causes aninferior chemical stability of the drug product (DP).

However, wet granulation of aliskiren using a mixture of organicsolvents or an organic binder solution has been found to be the best wayof manufacturing suitable aliskiren solid oral dosage forms, especiallytablets, showing following advantages:

-   -   Said wet granulation reduces the bulk volume of aliskiren during        granulation;    -   The influences of a changing drug substance quality are        minimized;    -   A high drug loading above 46% by weight per unit dosage form may        easily be achieved;    -   The formulation of tablets with sufficient hardness, resistance        to friability, disintegration time, dissolution rate etc. is        possible;    -   The sticking tendency and poor flow of the drug substance is        reduced to a minimum;    -   A robust manufacturing process of the DP is achieved;    -   Scale-up of formulation and process resulting in a reproducible        DP performance is achieved; and    -   Sufficient stability to achieve a reasonable shelf life is        achieved.

The excipients may be distributed partly in the inner (granular) phaseand partly in the outer phase, which is the case in the describedinvention. Microcrystalline cellulose (filler) and CROSPOVIDONE(disintegrant) are partly in the inner and partly in the outer phase,PVP K 30 (binder) is only part of the inner phase, being the binderduring granulation, whereas colloidal silicon dioxide (glidant) and Mgstearate (lubricant) are only part of the outer phase.

The inner phase excipients, e.g., filler, binder and disintegrant, andthe drug substance are mixed and granulated with an ethanolic solutionof the binder and additional ethanol. The granulate is dried and sieved.The outer phase containing, e.g., disintegrant, filler, glidant andlubricant, is screened with the dried granulate and mixed. The mixtureis compressed into tablets. The cores may optionally be coated with afilm-coat.

The granulate phase is defined as the inner phase, the excipients addedto the granulate are defined as the outer phase of the tablettingmixture.

The invention likewise relates to a process for the preparation of solidoral dosage forms as described herein above. Such solid oral dosage formmay be produced by working up components as defined herein above in theappropriate amounts, to form unit dosage forms.

Accordingly, the present invention provides a process for themanufacture of a solid oral dosage form of the present inventioncomprising:

-   1) mixing the active ingredient and additives and granulating said    components with a granulation liquid;-   2) drying a resulting granulate;-   3) mixing the dried granulate with outer phase excipients;-   4) compressing a resulting mixture to form a solid oral dosage as a    core tablet; and-   5) optionally coating a resulting core tablet to give a film-coated    tablet.

Preferably, the additives in step (1) are selected from a filler, adisintegrant and a binder; and the outer phase excipients in step (3)are selected from a filler, a disintegrant, a lubricant and a glidant.

The granulation liquid can be ethanol, a mixture of ethanol and water, amixture of ethanol, water and isopropanol, or a solution of PVP in thebefore mentioned mixtures. A preferred mixture of ethanol and waterranges from about 50/50 to about 99/1 (% w/w), most preferrably it isabout 94/6 (% w/w). A preferred mixture of ethanol, water andisopropanol ranges from about 45/45/5 to about 98/1/1 (% w/w/w), mostpreferably from about 88.5/5.5/6.0 to about 91.5/4.5/4.0 (% w/w/w). Apreferred concentration of PVP in the above named mixtures ranges fromabout 5 to about 30% by weight, preferably from about 15 to about 25%,more preferably from about 16 to about 22%.

Attention is drawn to the numerous known methods of granulating, dryingand mixing employed in the art, e.g., spray granulation in a fluidizedbed, wet granulation in a high-shear mixer, melt granulation, drying ina fluidized-bed dryer, mixing in a free-fall or tumble blender,compressing into tablets on a single-punch or rotary tablet press.

The manufacturing of the granulate can be performed on standardequipment suitable for organic granulation processes. The manufacturingof the final blend and the compression of tablets can also be performedon standard equipment.

For example, step (1) may be carried out by a high-shear granulator,e.g., Collette Gral; step (2) may be conducted in a fluid-bed dryer;step (3) may be carried out by a free-fall mixer (e.g. containerblender, tumble blender); and step (4) may be carried out using a drycompression method, e.g., a rotary tablet press.

As described above, the core tablets may then be optionally film-coated.

Due to the high hygroscopicity and water sensitivity of aliskiren withrespect to changes in polymorphism, the use of water has preferably tobe avoided in order to prevent the drug substance from changes inpolymorphism for the above stated reasons (amorphous state, inferiorchemical stability). A solution for said problem is to apply an organicfilm-coating process.

Surprisingly it was found that an aqueous film coating process using astandard film-coat composition can be applied to aliskiren core tabletswithout changes in polymorphism.

The film-coat preferably consists of HPMC as the polymer, iron oxidepigments, titanium dioxide as coloring agent, PEG as softener and talcas anti-tacking agent. The use of coloring agents or dyes may serve toenhance the appearance as well as to identify the compositions. Otherdyes suitable for use typically include carotinoids, chlorophyll andlakes.

The film coating conditions have to assure that the tablet cores do nottake up considerable amounts of moisture and that the drug substancewithin the tablets does not closely get into contact with waterdroplets. This is achieved by process parameter settings that reduce theamount of humidity which gets onto the tablet cores.

The solid oral dosage forms of the present invention are useful forlowering the blood pressure, either systolic or diastolic or both. Theconditions for which the instant invention is useful include, withoutlimitation, hypertension (whether of the malignant, essential,reno-vascular, diabetic, isolated systolic, or other secondary type),congestive heart failure, angina (whether stable or unstable),myocardial infarction, artherosclerosis, diabetic nephropathy, diabeticcardiac myopathy, renal insufficiency, peripheral vascular disease, leftventricular hypertrophy, cognitive dysfunction (such as Alzheimer's) andstroke, headache and chronic heart failure.

The present invention likewise relates to a method of treatinghypertension (whether of the malignant, essential, reno-vascular,diabetic, isolated systolic, or other secondary type), congestive heartfailure, angina (whether stable or unstable), myocardial infarction,artherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renalinsufficiency, peripheral vascular disease, left ventricularhypertrophy, cognitive dysfunction, e.g., Alzheimer's, stroke, headacheand chronic heart failure comprising administering to an animal,including human patient, in need of such treatment a therapeuticallyeffective solid oral dosage form according to the present invention.

The present invention likewise relates to the use of a solid oral dosageform according to the present invention for the manufacture of amedicament for the treatment of hypertension (whether of the malignant,essential, reno-vascular, diabetic, isolated systolic, or othersecondary type), congestive heart failure, angina (whether stable orunstable), myocardial infarction, artherosclerosis, diabeticnephropathy, diabetic cardiac myopathy, renal insufficiency, peripheralvascular disease, left ventricular hypertrophy, cognitive dysfunction,e.g., Alzheimer's, stroke, headache and chronic heart failure.

The present invention likewise relates to a pharmaceutical compositionfor the treatment of hypertension (whether of the malignant, essential,reno-vascular, diabetic, isolated systolic, or other secondary type),congestive heart failure, angina (whether stable or unstable),myocardial infarction, artherosclerosis, diabetic nephropathy, diabeticcardiac myopathy, renal insufficiency, peripheral vascular disease, leftventricular hypertrophy, cognitive dysfunction, e.g., Alzheimer's,stroke, headache and chronic heart failure, comprising a solid oraldosage form according to the present invention.

Ultimately, the exact dose of the active agent and the particularformulation to be administered depend on a number of factors, e.g., thecondition to be treated, the desired duration of the treatment and therate of release of the active agent. For example, the amount of theactive agent required and the release rate thereof may be determined onthe basis of known in vitro or in vivo techniques, determining how longa particular active agent concentration in the blood plasma remains atan acceptable level for a therapeutic effect.

The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspecifically disclosed herein are within the scope of the followingclaims. Without further elaboration, it is believed that one skilled inthe art can, using the preceding description, utilize the presentinvention to its fullest extent. Therefore, the Examples herein are tobe construed as merely illustrative and not a limitation of the scope ofthe present invention in any way.

Example 1

Composition of aliskiren 150 mg (free base) uncoated tablets in mg/unit.

Roller compacted Dosage Dosage Dosage Component tablet form 1 form 2form 3 Aliskiren hemi- 165.750 165.750 165.750 165.750 fumarateMicrocrystalline 220.650 84.750 72.250 107.250 cellulosePolyvinylpyrrolidon — — 12.000 12.000 K 30 Crospovidone 84.000 45.00044.000 48.200 Aerosil 200 4.800 1.500 1.500 1.800 Magnesium stearate4.800 3.000 4.500 5.000 Total weight 480.000 300.000 300.000 340.000

Composition of aliskiren 150 mg (free base) uncoated tablets in % byweight.

Roller compacted Dosage Dosage Dosage Component tablet form 1 form 2form 3 Aliskiren hemi- 34.53 55.25 55.25 48.75 fumarate Microcrystalline45.97 28.25 24.08 31.545 cellulose Polyvinylpyrrolidon — — 4 3.53 K 30Crospovidone 17.5 15 14.67 14.175 Aerosil 200 1 0.5 0.5 0.53 Magnesiumstearate 1 1 1.5 1.47 Total % 100.00 100.00 100.00 100.00

Composition of aliskiren 150 mg (free base) uncoated tablets in mg/unit(divided into inner/outer phase).

Roller compacted Dosage Dosage Dosage Component tablet form 1 form 2form 3 Inner Aliskiren hemi- 165.75 165.75 165.75 165.75 Phase fumarateMicrocrystalline 220.65 84.75 72.25 90.25 cellulose Polyvinylpyrrolidon— — 12.00 12.00 K 30 Crospovidone 36.00 — — 14.20 Aerosil 200 — — — —Magnesium stearate 2.40 — — — Outer Crospovidone 48.00 45.00 44.00 34.00phase Microcrystalline — — — 17.00 cellulose Aerosil 200 4.80 1.50 1.501.80 Magnesium stearate 2.40 3.00 4.50 5.00 Total weight 480.00 300.00300.00 340.00

Composition of aliskiren 150 mg (free base) uncoated tablets in % byweight (divided into inner/outer phase).

Roller compacted Dosage Dosag Dosage Component tablet form 1 form 2 form3 Inner Aliskiren hemi- 34.53 55.25 55.25 48.75 Phase fumarateMicrocrystalline 45.97 28.25 24.08 26.545 cellulose Polyvinylpyrrolidon— — 4 3.530 K 30 Crospovidone 7.5 — — 4.175 Aerosil 200 — — — —Magnesium stearate 0.5 — — — Outer Crospovidone 10 15 14.67 10 phaseMicrocrystalline — — — 5 cellulose Aerosil 200 1 0.5 0.5 0.53 Magnesiumstearate 0.5 1 1.5 1.47 Total % 100.00 100.00 100.00 100.00

Example 2

Composition of aliskiren (dosage form 3) film-coated tablets in mg/unit.

Dosage form 3/Strength 75 mg 150 mg 300 mg Component (free base) (freebase) (free base) Aliskiren 82.875 165.750 331.500 hemi-fumarateMicrocrystalline 53.625 107.250 214.500 cellulose Polyvinylpyrrolidon6.000 12.000 24.000 K 30 Crospovidone 24.100 48.200 96.400 Aerosil 2000.900 1.800 3.600 Magnesium stearate 2.500 5.000 10.000 Total tabletweight 170.000 340.000 680.000 Opadry premix white 9.946 16.711 23.9616Opadry premix red 0.024 0.238 1.8382 Opadry premix black 0.030 0.0510.2002 Total fim-coated 180.000 357.000 706.000 tablet weight

What is claimed is:
 1. A solid oral dosage form comprising atherapeutically effective amount of aliskiren, or a pharmaceuticallyacceptable salt thereof, in an amount of more than 46% by weight basedon the total weight of the oral dosage form, wherein the oral dosageform is in the form of a tablet and comprises a) an inner phase which iscomprising aliskiren or a pharmaceutically acceptable salt thereof,microcrystalline cellulose, polyvinylpyrrolidone, and crosslinkedpolyvinylpyrrolidone, and b) an outer phase which is comprisingcrosslinked polyvinylpyrrolidone, microcrystalline cellulose, colloidalsilicon dioxide, and magnesium stearate and wherein the amount ofmicrocrystalline cellulose in the dosage form ranges from 20 to 32% byweight, the amount of crosslinked polyvinylpyrrolidone in the dosageform ranges from 13.5 to 16% by weight, the amount ofpolyvinylpyrrolidone in the dosage form ranges from 3 to 4% by weight,the amount of colloidal silicon dioxide in the dosage form ranges from0.4 to 0.6% by weight, and the amount of magnesium stearate in thedosage form ranges from 0.2 up to 5% by weight.
 2. The solid oral dosageform according to claim 1, wherein the tablet further comprises a filmcoat wherein said film coat comprises a filmcoating material selectedfrom hydroxypropyl methyl cellulose, polyethylene glycols,polyvinylpyrrolidones, polyvinylpyrrolidone-vinyl acetate copolymer,polyvinyl alcohol, and sugar.
 3. The solid oral dosage form according toclaim 1, wherein the tablet is chosen from a tablet in the form ofmultiparticulates, multiparticulate pellets, multiparticulateminitablets, wax matrix systems, polymer matrix tablets, polymer coatedtablets, oral osmotic systems, coated tablets, matrix tablets,press-coated tablets, and multilayer tablets.
 4. A solid oral dosageform according to claim 1, wherein the active ingredient is present inan amount of more than 48% by weight.
 5. A solid oral dosage formaccording to claim 1, wherein the active ingredient is present in anamount ranging from 46 to 60% by weight.
 6. A solid oral dosage formaccording to claim 1, wherein the active ingredient consists entirely ofaliskiren, or a pharmaceutically acceptable salt thereof, and is presentin an amount ranging from about 75 to about 600 mg of the free base perunit dosage form.
 7. A solid oral dosage form according to claim 1,wherein the active ingredient consists entirely of aliskiren, or apharmaceutically acceptable salt thereof, and is present in an amountranging from about 75 to about 300 mg of the free base per unit dosageform.
 8. A solid oral dosage form according to claim 7, whereinaliskiren is in the form of a hemi-fumarate thereof, and is present inan amount of about 83 mg per unit dosage form.
 9. A solid oral dosageform according to claim 8, wherein aliskiren is in the form of ahemi-fumarate thereof, and is present in an amount of about 166 mg perunit dosage form.
 10. A solid oral dosage form according to claim 6,wherein aliskiren is in the form of a hemi-fumarate thereof, and ispresent in an amount of about 332 mg per unit dosage form.
 11. A solidoral dosage form according to claim 1 for use in the manufacture of amedicament for the treatment of hypertension.
 12. A solid oral dosageform according to claim 1, wherein the active ingredient is present inan amount of more than 46% up to 56% by weight.
 13. A solid oral dosageform according to claim 2, wherein the filmcoating material ishydroxypropyl methyl cellulose.
 14. A solid oral dosage form accordingto claim 2 or 13, wherein the film coat further comprises additivesselected from pigments, dies, titanium dioxide, iron oxides, talc, andpolyethylene glycols 3350, 4000, 6000 and
 8000. 15. A solid oral dosageform according to claim 2, wherein the film coat comprises hydroxypropylmethyl cellulose, iron oxide pigments, titanium dioxide, polyethyleneglycol, and talc.
 16. A solid oral dosage form according to claim 1comprising 82.875 mg aliskiren hemifumarate; 53.625 mg microcrystallinecellulose; 6 mg polyvinylpyrrolidone; 24.1 mg crosslinkedpolyvinylpyrrolidone; 0.9 mg colloidal silicon dioxide; and 2.5 mgmagnesium stearate.
 17. A solid oral dosage form according to claim 1comprising 165.75 mg aliskiren hemifumarate; 107.25 mg microcrystallinecellulose; 12 mg polyvinylpyrrolidone; 48.2 mg crosslinkedpolyvinylpyrrolidone; 1.8 mg colloidal silicon dioxide; and 5 mgmagnesium stearate.
 18. A solid oral dosage form according to claim 1comprising 331.5 mg aliskiren hemifumarate; 214.5 mg microcrystallinecellulose; 24 mg polyvinylpyrrolidone; 96.4 mg crosslinkedpolyvinylpyrrolidone; 3.6 mg colloidal silicon dioxide; and 10 mgmagnesium stearate.
 19. A method for the treatment of hypertension,congestive heart failure, angina, myocardial infarction,artherosclerosis, diabetic nephropathy, diabetic cardiac myopathy, renalinsufficiency, peripheral vascular disease, left ventricularhypertrophy, cognitive dysfunction, stroke, headache and chronic heartfailure which method comprises administering a therapeutically effectiveamount of a solid oral dosage form according to claim 1 to a patient inneed thereof.
 20. A process for the manufacture of a solid oral dosageform according to claim 1 comprising: 1) mixing the active ingredientand microcrystalline cellulose, polyvinylpyrrolidone, and crosslinkedpolyvinylpyrrolidone and granulating said components with a granulationliquid; 2) drying a resulting granulate; 3) mixing the dried granulatewith crosslinked polyvinylpyrrolidone, microcrystalline cellulose,colloidal silicon dioxide, and magnesium stearate; 4) compressing aresulting mixture to form a solid oral dosage as a core tablet; and 5)optionally coating a resulting core tablet to give a film-coated tablet.